FOR MAJOR BLEEDING related to severe trauma, major

Transcription

1 REVIEW ARTICLE Paul G. Barash, MD Giovanni Landoni, MD Section Editors Rotational Thromboelastometry (ROTEM)-Based Coagulation Management in Cardiac Surgery and Major Trauma Kenichi A. Tanaka, MD, MSc,* Daniel Bolliger, MD, Ratna Vadlamudi, MD, and Alastair Nimmo, MB FOR MAJOR BLEEDING related to severe trauma, major surgery, or chronic anticoagulation, a rapid assessment of hemostatic function is crucial so that optimal fluid replacements and blood transfusion can be administered without delays. 1-6 Although the safety of blood products with regard to viral transmission risks has improved in recent years, 7,8 transfusions of allogeneic erythrocyte and plasma products have been implicated in serious adverse events, including nosocomial infections, acute lung injury, and organ dysfunction Obtaining conventional laboratory tests, such as the prothrombin time (PT), activated partial thromboplastin time (aptt), and fibrinogen level, during acute bleeding is difficult because of a long turn-around time ( 30 min). 13,14 Furthermore, laboratory PT/international normalized ratio and aptt may not be particularly useful in predicting bleeding after trauma or invasive procedures. 15,16 The prime example of bleeding management is preemptive transfusions of fresh-frozen plasma (FFP) and platelet concentrates according to the erythrocyte requirement in major trauma cases. 17,18 This so-called damage control resuscitation (DCR; Table 1) originally was advocated for battlefield resuscitation in which laboratory testing and transfusion resources were limited. However, plasma product transfusion according to DCR became increasingly popular in US civilian trauma centers and operating rooms. 17,19 The prevention of trauma-induced coagulopathy and subsequent nonsurgical bleeding is a major advantage of DCR, 20 but the DCR approach lacks a specific target for replacement and a consideration for interindividual variability in coagulation factor levels and vascular (endothelial) responses. Implementing transfusion algorithms based on point-of-care (POC) coagulation testing can be effective in decreasing transfusion requirements in elective or urgent cardiac surgical settings. 2,5,21-23 In this review, the practical use of thromboelastometry is discussed relating to the diagnosis of coagulopathy and optimizing hemostatic interventions. POC TESTING AND TIMING OF HEMOSTATIC INTERVENTION PT (or international normalized ratio), aptt, fibrinogen level (Clauss method and its modifications), and platelet count are the tests performed most commonly in managing perioperative bleeding. Except for the platelet count, these laboratory tests require a separation of plasma from whole blood before testing, and, thus, a typical turn-around time is in the range of minutes. 13,24 Abnormalities detected in these tests are followed by requests for specific blood components. The choice of hemostatic therapies also affects the lag time before intervention. The time required for thawing FFP and cryoprecipitate is typically minutes, but less time is needed for platelet concentrates and thawed plasma. Factor concentrates, such as fibrinogen concentrate, and recombinant activated factor VII (rfviia) can be administered rapidly ( 10 min) because they are reconstituted in small volumes and infused irrespective of blood type. One of the key facts behind DCR is to prevent the delay of transfusion therapy for patients in whom the risk of hemorrhagic death is considerably greater than transfusion-associated complications. 25 However, a substantial number of patients may receive allogeneic plasma products inappropriately or in excess, which collectively increase the risk for transfusionrelated adverse events. 26 By implementing rapid POC coagulation testing, hemostatic interventions can be more individualized and goal directed (targeted) instead of indiscriminate applications of DCR. Currently available POC coagulation tests are classified into 3 categories. The first category includes POC whole-blood PT and aptt for a rapid evaluation (5-10 min) of plasmatic coagulation. POC PT has been shown to have a reasonable agreement with plasma-based PT. 13,27,28 However, PT and aptt are sensitive only to severe hypofibrinogenemia ( mg/dl) and are insensitive to FXIII deficiency or From the *Department of Anesthesiology, University of Pittsburgh Medical Center, Pittsburgh, PA; Department of Anesthesia and Intensive Care Medicine, University of Basel Hospital, Basel, Switzerland; Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA; and Royal Infirmary of Edinburgh, Edinburgh, UK. Dr Bolliger was supported by a Myron B. Laver Grant, Department of Anaesthesia, University of Basel, Switzerland. Drs Tanaka, Bolliger, and Nimmo have received honoraria for consultation and/or lectures from TEM International (Munich, Germany). Address reprint requests to Kenichi A. Tanaka, MD, MSc, Visiting Professor of Anesthesiology, Department of Anesthesiology, UPMC Presbyterian C-215, 200 Lothrop Street, Pittsburgh, PA atlclot7@me.com 2012 Elsevier Inc. All rights reserved /xx0x-0001$36.00/0 Key words: rotational thromboelastometry, coagulation monitoring, blood component transfusion, cardiac surgery, trauma Journal of Cardiothoracic and Vascular Anesthesia, Vol xx, No x (Month), 2012: pp xxx 1

2 2 TANAKA ET AL Table 1. Damage Control Resuscitation Early surgical control of bleeding sites Early transfusion of plasma, platelets, and erythrocytes; minimized crystalloid usage Permissive hypotension (mean arterial pressure 60 mmhg) Correction of hypothermia and acidosis Timely use of CaCl 2, THAM, and rfviia Abbreviations: rfviia, recombinant factor VIIa; THAM, tris-hydroxymethyl aminomethane (alkalizer). fibrinolysis. 29 Further, PT and aptt have different sensitivities to hemodilution-induced decreases in procoagulant factor levels, 15,16 and neither test reflects the total amount of thrombin that can be generated in plasma. 24 The second category includes whole-blood platelet function tests, which are used increasingly to monitor therapeutic responses to aspirin, clopidogrel, and other platelet adenosine-5=-diphosphate antagonists. 30,31 Evaluating the extent of platelet inhibition by antiplatelet agents may be useful in optimizing the perioperative risks of thrombosis and hemorrhage. 32,33 Although a detailed discussion of platelet function monitoring is beyond the scope of this review, PlateletMapping will be discussed later as a modified technique of thrombelastography (TEG; Haemonetics-Haemoscope, Niles, IL). 34 The third category includes TEG and rotational thromboelastometry (ROTEM; TEM Systems, Raleigh, NC). These 2 systems are suitable for timely decision making ( 20 min) in hemostatic interventions. 2,4-6 Indeed, the decrease of postoperative blood loss without increasing the blood component usage or mortality has been shown in a recent metaanalysis, including TEG and ROTEM. 35 Rapid detection of coagulopathy by TEG or ROTEM allows a timely preparation (thawing) of blood products or a prompt intervention using plasma-derived or recombinant factor concentrate. 4-6,36,37 COAGULATION TESTING ON ROTEM The basic principles and technical aspects of TEG and ROTEM have been reviewed elsewhere. 14,38-40 In this article, the practical applications of ROTEM are described because this system currently offers comprehensive tests of coagulation. For standard ROTEM measurements, a citrated whole-blood sample (300 L) is placed in a plastic cup using an automated pipette (Fig 1). The sample is recalcified with CaCl 2, 0.2 mmol/l (StarTEM; 20 L) and activated with 20 L ofan EXTEM (tissue factor [TF]) or INTEM (ellagic acid) reagent. Subsequently, the plastic pin is immersed in the blood. Once thrombin is generated in the blood, platelets are activated to express glycoprotein (GP) IIb/IIIa receptors, and fibrin is formed and polymerized. The interactions of GP IIb/IIIa receptors and polymerized fibrin increase the torque (viscoelasticity) between the cup and the rotating pin (at a 4.75 angle). The breakdown of fibrin strands by fibrinolysis decreases the torque. The change in torque is detected optically and is processed by the microprocessor to trace the clot formation and breakdown. The commonly used ROTEM variables include coagulation time (CT; seconds), clot formation time (seconds), -angle (degrees), amplitude at 10 minutes after CT (A10; millimeters), Diode Light detector Data processor Clot firmness (mm) CT CFT Alpha A10 MCF ML CT Clotting time CFT Clot formation time Alpha Alpha angle A10 Amplitude 10 min after CT MCF Maximum clot firmness ML Maximum lysis Time (min) Pin Blood Fig 1. Basic principles of rotational thromboelastometry. For a rotational thromboelastometric measurement, a citrated blood sample is placed with CaCl 2 and a coagulation activator in the stationary cup. The rotating pin is lowered into the blood, and subsequent clot formation changes the torque between the pin and the cup. The measured rotational thromboelastometric variables include the coagulation time (CT; seconds), clot formation time (CFT; seconds), -angle (degrees), amplitude at 10 minutes after CT (A10; millimeters), maximum clot firmness (MCF; millimeters), and maximum lysis (ML; percent decrease in amplitude 60 min after MCF). (Color version of figure is available online.)

3 ROTEM IN COAGULATION MANAGEMENT 3 Table 2. Indications and Reference Ranges of Rotational Thromboelastometric Tests Tests Indicated to Evaluate CT (s) CFT (s) A10 (mm) MCF (mm) ML (%) EXTEM, APTEM 2platelets, 2plasma factors, 1fibrinolysis (55) (95) (53) (60) 0-18 (4) FIBTEM 2fibrinogen 9-24 (14) 9-25 (16) INTEM, HEPTEM 2platelets, 2plasma factors, 1heparin (184) (63) (55) (61) 0-12 (3) NOTE. Normal ranges (medians) are shown for EXTEM, FIBTEM, and INTEM. The EXTEM reference range is used for APTEM and the INTEM reference range is used for HEPTEM. Data from Lang et al. 41 Abbreviations: A10, amplitude at 10 minutes after coagulation time; APTEM, modified EXTEM test with aprotinin; CT, coagulation time; EXTEM, tissue factor reagent; FIBTEM, modified EXTEM test with cytochalasin D; FFP, fresh-frozen plasma; HEPTEM, heparinase plus INTEM reagent; INTEM, ellagic acid reagent; MCF, maximum clot firmness; ML, maximum lysis (percent decrease in amplitude 60 min after MCF); PCC, prothrombin complex concentrate; TXA, tranexamic acid. maximum clot firmness (MCF; millimeters), and maximum lysis (ML; percent decrease in amplitude 60 min after MCF; Fig 1). CT represents the onset of coagulation, whereas the clot formation time and -angle represent the initial rate of fibrin polymerization. MCF is a measurement of the maximal viscoelastic strength of the clot. An ML 15% is used for the diagnosis of a premature breakdown of clot (hyperfibrinolysis). Normal ranges are summarized in Table The reference ranges of TEG differ from those of ROTEM because of different sample types (citrated v noncitrated) and coagulation activators (kaolin v INTEM or EXTEM). 39 In addition to EXTEM and INTEM, several other tests can be used in conjunction to diagnose specific coagulation problems. FIBTEM is a modified EXTEM test (Fig 2A) with cytochalasin D, which inhibits platelet cytoskeletal reorganization and, thus, fibrin(ogen) binding to platelet GP IIb/IIIa. 42 By combining EXTEM and FIBTEM, the differential diagnosis of thrombocytopenia and/or hypofibrinogenemia is feasible within 20 minutes (Fig 2B, C). APTEM is also a modified EXTEM, in which aprotinin inhibits plasmin in vitro if systemic fibrinolysis was present (Fig 2D). 37 HEPTEM contains heparinase in addition to the INTEM reagent. It is used as a pair with INTEM for the diagnosis of systemic heparin activity (Fig 2E). 43 Although INTEM and kaolin-activated TEG are intrinsic pathway tests, the sensitivity and specificity are considerably different. Therefore, the cutoff values for ROTEM cannot be applied simply to TEG. 39 HEMOSTATIC MECHANISMS IN VIVO In the event of a vascular injury (Fig 3A), a localized hemostatic response is triggered by subendothelial collagen and TF, which are exposed to the circulating blood. Circulating platelets play a particularly important role in arterial hemostasis. The initial tethering of platelets to collagen is mediated by platelet GP Ib/IX and the von Willebrand factor. A transient binding of platelets to the von Willebrand factor becomes stabilized by collagen-induced platelet activation (via 2 1 and GP VI receptors). 44 In parallel, a trace amount of thrombin is generated by TF-FVIIa/FXa (extrinsic pathway). Thus, adenosine-5=-diphosphate and thromboxane are released by collagen- and thrombin-activated platelets, forming the primary hemostatic plug (Fig 3B). Subsequently, platelet aggregates serve as catalytic surfaces and binding sites for coagulation responses. Substrates (fibrinogen), proenzymatic factors (FII, FIX, FX, FXI, FXIII), and accelerators (FV, FVIII) are congregated (depicted as S-E-A in Fig 3C) on the activated platelet surface to augment the local generation of thrombin and polymerized fibrin. After the initial activation of thrombin by the extrinsic pathway, the propagation of thrombin formation mainly involves the intrinsic pathway. Thrombin can activate FXI, which efficiently converts FIX to FIXa. On the activated platelet surface, FIXa in combination with thrombin-activated FVIIIa becomes the major activator (intrinsic tenase) of FX. Subsequently, FXa and thrombin-activated FVa form a complex (prothrombinase), which exponentially increases the conversion of prothrombin (FII) to thrombin. Once activated by adenosine-5=-diphosphate-stimulated, each platelet expresses a large number of GP IIb/IIIa receptors ( 12,000) for fibrinogen binding. 45 Platelet-bound fibrinogen is converted to a fibrin monomer by thrombin. Fibrin monomers are polymerized by plasma and platelet-derived FXIIIa, a transglutaminase, which requires thrombin-mediated activation. 46 Polymerization of fibrin on platelets stabilizes the primary hemostatic plug. 47 On ROTEM and TEG, major hemostatic responses involving thrombin-activated platelets (GP IIb/IIIa), fibrin, and FXIIIa are reflected, although the contributions of the von Willebrand factor, platelet GP Ib/IX, and other platelet agonists are minimal. HEMOSTATIC INTERVENTIONS It is well known that blood transfusion practice varies among individuals and institutions. 48 In case of bleeding, FFP, platelet concentrates, and cryoprecipitate often are transfused empirically without laboratory testing. In addition to these allogeneic products, plasma-derived or recombinant factor concentrates, such as fibrinogen concentrates, prothrombin complex concentrates, and rfviia, have been used for perioperative hemostasis. 6,49 Recent clinical data have shown that ROTEM testing is a practical method to standardize the local transfusion practice. 5,50,51 Normal ranges of ROTEM testing are based on a multicenter study in healthy adult volunteers (Table 2). 41 Hemostatic intervention(s) should be considered for nonsurgical bleeding in the presence of abnormal ROTEM results. Threshold ROTEM values for interventions may vary among different types of vascular injury. In this section, several hemostatic products are discussed in relation to ROTEM parameters, but the availability of products differs among institutions and countries. Therefore, it is prudent to validate or modify the herein-described algorithm for suitability at each institution.

4 4 TANAKA ET AL A. E EXTEM CT MCF 58 mm FIBTEM MCF 13 mm B. EXTEM min MCF mm FIBTEM min MCF 9 mm C min min EXTEM MCF 38 mm FIBTEM MCF 4 mm min min D. EXTEM APTEM ML 100% ML 0% min min E. INTEM HEPTEM CT 1500 s CT 205 s min min Fig 2. Examples of rotational thromboelastometric tracings. (A) Normal (EXTEM, FIBTEM): EXTEM-MCF (normal, mm) and FIBTEM (normal, 9-25 mm). (B) Thrombocytopenia (EXTEM, FIBTEM): platelet count /L and fibrinogen 170 mg/dl. (C) Thrombocytopenia and hypofibrinogenemia (EXTEM, FIBTEM): platelet count /L and fibrinogen 78 mg/dl. (D) Systemic fibrinolysis (EXTEM, APTEM): normal ML is <15%. (E) Heparin effect (INTEM, HEPTEM): prolonged CT (1,500 s) at INTEM (normal range, s) is corrected at HEPTEM (ie, CT INTEM /CT HEPTEM 1.0 in the absence of heparin). APTEM, modified EXTEM test with aprotinin; CT, coagulation time; EXTEM, tissue factor reagent; FIBTEM, modified EXTEM test with cytochalasin D; HEPTEM, heparinase plus INTEM reagent; INTEM, ellagic acid reagent; MCF, maximum clot firmness; ML, maximum lysis (percent decrease in amplitude 60 min after MCF). (Color version of figure is available online.)

5 ROTEM IN COAGULATION MANAGEMENT 5 Event Elements Interventions (a) Vascular injury (b) Primary hemostasis (c) Coagulation Vascular injury Bleeding Collagen Tissue factor Erythrocytes S-E-A Primary hemostasis Localization of factors Platelets ADP, Thromboxane vwf, Fibrinogen FVII, FX, FII Platelets Cryoprecipitate vwf concentrate Desmopressin S-E-A Thrombin generation Fibrin polymerization Platelets (S) Fibrinogen (E) FII, FIX, FX, FXI, FXIII (A) FV, FVIII FFP, PCC Cryoprecipitate Fibrinogen FXIII concentrate rfviia Fig 3. Hemostatic processes and phase-specific interventions. (A) Hemorrhage occurs after vascular injury. Extravascular (subendothelial) collagen and tissue factor are exposed to the flowing blood. Transfusion of erythrocytes is the initial intervention. The intact vascular wall (blue), platelets (white ovals), erythrocytes (red circles), and fibrin (green) are depicted. (B) Platelets adhere to the vascular injury site by interacting with von Willebrand factor (vwf) by glycoprotein Ib/IX receptors. Mural platelets are activated by collagen and trace thrombin (by the extrinsic pathway involving factors VII [FVII], X [FX], and II [FII]). They release adenosine-5=-diphosphate (ADP) and thromboxane, stabilizing platelet-platelet interactions with fibrinogen. Thus, the primary (hemostatic) plug is established. Platelet transfusion and measures to increase von Willebrand factor can augment this process. (C) Activated platelet aggregates serve as a catalytic surface and binding sites for coagulation responses. Substrates (S; fibrinogen), proenzymatic factors (E; factors II, IX [FIX], X, XI [FXI], and XIII [FXIII]), and accelerators (A; factors V [FV] and VIII [FVIII]) are congregated. These factors can be replaced using freshfrozen plasma (FFP) or specific factor concentrates (see text for details). PCC, prothrombin complex concentrate; rfviia, recombinant factor VIIa. Platelets The clot firmness of EXTEM shows the tensile strength of the whole-blood clot, which reflects the interaction between thrombin-activated platelets and polymerized fibrin via platelet GP IIb/IIIa receptors. For microvascular bleeding, EXTEMand FIBTEM-A10 values can be used differentially to diagnose the need for platelet transfusion or fibrinogen replacement. Thrombocytopenia ( /L) is suspected when the EXTEM-MCF is 45 mm and the FIBTEM-MCF is 8-10 mm (Table 3). 5,52 When the FIBTEM-MCF is 10 mm, cryoprecipitate or fibrinogen is withheld unless bleeding is likely to continue and lower fibrinogen levels. Platelet transfusion and fibrinogen replacement usually are indicated when the EXTEM-MCF is 35 mm. 5,53 When the EXTEM-MCF is 45 mm, severe thrombocytopenia ( /L) is unlikely, but hereditary platelet dysfunction or antiplatelet effects of aspirin and P 2 Y 12 antagonists (ticlopidine, clopidogrel, prasugrel, etc) may not be excluded. Platelet function tests can be used preoperatively to screen high-risk patients. PFA-100 (Siemens, Tarrytown, NY) can be useful in screening patients with von Willebrand disease or a platelet GP Ib defect (Bernard-Soulier syndrome). 54 The VerifyNow system (Accumetrics, Inc., San Diego, CA) and whole-blood impedance aggregometry (Multiplate, DynaBite, Munich, Germany) are used increasingly to monitor therapeutic responses to aspirin and P 2 Y 12 antagonists. 32,55 For TEG, PlateletMapping is available for the evaluation of platelet inhibition by aspirin or clopidogrel. 34,56-58 For this assay, a heparin-anticoagulated blood sample is used specifically to inhibit thrombin, which masks the antiplatelet effects of aspirin and clopidogrel. For PlateletMapping, fibrin polymerization is achieved by the mixture of reptilase and activated FXIII. Platelets are activated separately by the specific platelet activator (arachidonic acid for aspirin and adenosine-5=-diphosphate for clopidogrel). Decreased maximum amplitudes on PlateletMapping compared with kaolin-activated TEG have been observed in perioperative patients with gross platelet inhibition by aspirin or clopidogrel. 59 Plasma and Prothrombin Complex Concentrate The CT of EXTEM or INTEM can be used in determining the need for administering FFP or prothrombin complex concentration (PCC). The latter refers to plasma-derived concentrates of vitamin K-dependent factors (FVII, FIX, FX, prothrombin, protein C, and protein S). 60 Coagulation factor replacements are considered when CT values are prolonged (EXTEM-CT 100 s or INTEM-CT 240 s) and when residual heparin effects, thrombocytopenia, and hypofibrinogenemia have been addressed appropriately (Table 3). In patients who have received intravenous heparin, a proper neutralization of heparin can be confirmed by equal CT values between INTEM and HEPTEM (Fig 2E). 43 Plasma or PCC can be used to correct a factor deficiency for a prolonged CT on HEPTEM. 5 Similar to PT and aptt, EXTEM-CT and INTEM-CT are defined as the onset of blood coagulation after activation with TF and ellagic acid, respectively. However, ROTEM-CT values are not equivalent to PT and aptt. In trauma-induced coagulopathy, the correlation between the CT value and PT/ aptt was found to be rather poor (r ). 61 The reaction time (equivalent of CT) of kaolin-activated TEG has been reported to correlate poorly with PT or aptt. 62,63 Abnormal PT/aPTT values ( 1.5 times normal) are found frequently when ROTEM parameters related to fibrin polymerization (EXTEM-A15 or clot formation time) are abnormal. 61 Severe hypofibrinogenemia ( mg/dl) can be the cause of prolonged CT and PT/aPTT. Fibrinogen-Rich Components Cryoprecipitate is used commonly in North America for fibrinogen replacement. In many European countries, this product is no longer available, and plasma-derived fibrinogen concentrate is used as a substitute. 5,6,64 The minimal level of fibrinogen previously was thought to be mg/dl. 65,66 However, higher fibrinogen levels ( mg/dl) have been recommended in recent guidelines It is plausible that a minimal fibrinogen level of mg/dl is adequate for congenital afibrinogenemia (ie, normal factor levels other than fibrinogen), but higher fibrinogen levels ( mg/dl) are necessary for a multifactorial deficiency associated with perioperative coagulopathy. 70 There are several published data that support the efficacy of fibrinogen-rich components. In pediatric

6 6 TANAKA ET AL Table 3. Hemostatic Interventions Based on Rotational Thromboelastometric Results EXTEM-MCF Parameters EXTEM-MCF Clot Firmness 35 mm mm 45 mm FIBTEM-MCF* 10 mm Cryo/fibrinogen Platelet 1 U Cryo/fibrinogen Platelet 1 U Cryo/fibrinogen 10 mm Platelets 1-2 U Platelet 1 U If bleeding is uncontrolled, consider FFP or PCC based on EXTEM-CT as below or consider platelet transfusion in patients on P 2 Y 12 inhibitors Diagnosis Management Prolonged CT Values INTEM-CT/HEPTEM-CT ratio 1.0 Residual heparin Protamine mg EXTEM-CT 100sor INTEM-CT 240 s Low coagulation factors FFP ml/kg or PCC 20 IU/kg FIBTEM-A10 5 mm Very low fibrinogen Cryo/fibrinogen as above ( 100 mg/dl) Fibrinolysis Patterns Fibrinolysis 20 min Fulminant fibrinolysis TXA 1-2 g or EACA 5-10 g Fibrinolysis min Early fibrinolysis TXA 1gorEACA 5 g Fibrinolysis 40 min Clot retraction or late fibrinolysis Usually no treatment is required Abbreviations: A10, amplitude at 10 minutes after coagulation time; APTEM, modified EXTEM test with aprotinin; Cryo, cryoprecipitate; CT, coagulation time; EACA, -aminocaproic acid; EXTEM, tissue factor reagent; FIBTEM, modified EXTEM test with cytochalasin D; FFP, fresh-frozen plasma; HEPTEM, heparinase plus INTEM reagent; INTEM, ellagic acid reagent; MCF, maximum clot firmness; PCC, prothrombin complex concentrate; TXA, tranexamic acid. *FIBTEM-A10 at 8 mm may be used as a cutoff instead of FIBTEM-MCF at 10 mm. For fibrinogen replacement, Cryo, 10 U, or plasma-derived fibrinogen concentrate, 2 g, is administered. If FIBTEM-A10 is 5 mm, the dose of Cryo or fibrinogen concentrate is doubled. EXTEM and APTEM are repeated after each therapeutic intervention. Antifibrinolytic agents are used only if the risk of bleeding is greater than the risk of thrombosis or worsening of disseminated intravascular coagulation. cardiac surgical patients (body weight 8 kg), Miller et al 71 reported that 24-hour chest tube drainage was greater after platelet and FFP transfusions compared with platelet and cryoprecipitate (39.8 v 20.2 ml/kg). These patients received FFP or cryoprecipitate when the platelet transfusion was not effective to correct microvascular bleeding. The post-treatment fibrinogen level was mg/dl in the platelet-ffp group versus mg/dl in the platelet-cryoprecipitate group. More recently, Rahe-Meyer et al 72 reported that perioperative blood usage (erythrocytes, FFP, and platelets) was decreased by maintaining a higher plasma fibrinogen level (mean, mg/dl) using a purified fibrinogen concentrate compared with the conventional management (mean fibrinogen, mg/dl) for replacement of the ascending aorta. The FIBTEM test has been used commonly in ROTEM for the clinical assessment of fibrin polymerization in whole blood. FIBTEM-MCF is well correlated with plasma fibrinogen levels (r ). 24,61 In trauma-induced coagulopathy, a FIB- TEM-A10 of 5 mm was reported to be a good predictor of low plasma fibrinogen ( 100 mg/dl), with a sensitivity of 91% and a specificity of 85%. 61 In patients after cardiopulmonary bypass (CPB), a FIBTEM-MCF of 10 mm was a good estimate of plasma fibrinogen at 200 mg/dl. 24,61 For microvascular bleeding, fluid resuscitation and blood loss continuously lower plasma fibrinogen. Therefore, it is reasonable to maintain a FIBTEM-MCF at 10 mm using a cryoprecipitate or fibrinogen concentrate (Table 3). FIBTEM testing can be performed in heparinized samples (eg, during CPB), and, therefore, hypofibrinogenemia can be detected early so that the cryoprecipitate can be thawed or fibrinogen concentrates can be prepared. 5,50,51 Recombinant Activated Factor VIIa The use of rfviia is indicated in hemophiliac patients who have developed neutralizing antibodies against FVIII or FIX. 73 Its use also is common in severe perioperative bleeding after cardiac surgery and major trauma. 74 The efficacy of rfviia to generate thrombin depends on the available TF. 75 High TF concentrations in PT and EXTEM make these tests insensitive for delineating the in vivo efficacy of rfviia in surgical patients 76 and in hemophiliac patients. 77 Alternatively, diluted TF (eg, innovin, 1:17,000) has been tried, with mixed results, in monitoring the therapeutic response to rfviia in hemophilia Kaolin-activated TEG has been used to evaluate the TF-independent hemostatic activity of rfviia in hemophilia. 81,82 In nonhemophiliac surgical patients, rfviia continues to be used as a second-line intervention after the failure of platelet and plasma transfusions. 76,83 In this regard, TEG and ROTEM can be used to diagnose major causes of bleeding, such as thrombocytopenia,

7 ROTEM IN COAGULATION MANAGEMENT 7 hypofibrinogenemia, and fibrinolysis, which preclude the optimal hemostatic effect of rfviia. 76,84-86 Antifibrinolytic Therapy Systemic fibrinolysis can be caused by an increased endothelial release of tissue plasminogen activator 87 or by a decreased protease inhibition of tissue plasminogen activator and plasmin. 85 In ROTEM, hyperfibrinolysis is suspected when the decrease of the amplitude over 1 hour is 15% of MCF (Table 3, Fig 2D). The APTEM test is a modified EXTEM test with added aprotinin (plasmin inhibitor) at ROTEM. The resolution of fibrinolysis on APTEM compared with EXTEM confirms ongoing systemic fibrinolysis. 14 In 15%-20% of patients with major trauma, overt hyperfibrinolysis is observed at ROTEM and TEG. 36,37,88 Even in the absence of systemic fibrinolysis, a fibrin clot tends to be more susceptible to a plasmin-mediated breakdown after hemodilution owing to a progressive loss of endogenous fibrinolysis inhibitors. 85 Using ROTEM, it may be feasible to use antifibrinolytic therapy selectively in patients at risk for systemic fibrinolysis, 89 which can be associated with severe injuries and increased mortality. 37,88 ROTEM-BASED TRANSFUSION ALGORITHMS IN CARDIAC SURGERY Cardiovascular surgical patients are at increased risk for vascular thrombosis associated with atheromatous vascular disease, atrial fibrillation, implanted coronary stents, and mechanical heart valves. 90 Antiplatelet and antithrombotic therapies often are prescribed for preoperative patients. Balancing the risk of thrombosis against hemorrhage is one of the most difficult tasks for perioperative physicians. 90,91 Intraoperatively, these patients are anticoagulated with heparin for CPB or vascular anastomosis. Hemorrhage and hemodilution decrease circulating levels of coagulation factors and inhibitors. 85 At the conclusion of surgery, heparin anticoagulation requires a prompt reversal using protamine to establish hemostasis (clot formation). Antifibrinolytic therapy with tranexamic acid or -aminocaproic acid commonly is used during CPB as a prophylactic measure to decrease bleeding. 92,93 However, the transfusion of allogeneic plasma and platelet products often is necessary to achieve hemostasis in complex CPB cases. 83,93 Transfusion algorithms using TEG or ROTEM have been shown previously to decrease postoperative blood loss and transfusion requirements in cardiac surgery. 2,22,23 An example of ROTEM-based coagulation management in cardiac surgery is presented (Fig 4). EXTEM and FIBTEM are insensitive to heparin ( 6 U/mL), and they can be tested toward the end of CPB (eg, rewarming). 50,51 Based on results (Table 3), hemostatic therapy after CPB can be planned in advance, which may decrease the long interval from protamine administration to hemostatic intervention(s). After the correction of surgical bleeding and metabolic parameters (eg, ph status, body temperature), a ROTEM-based protocol allows patient-specific hemostatic therapy targeted to replace deficient coagulation element(s) rather than indiscriminately transfusing platelets and plasma products. 94 The initial approach to hemostasis generally involves the restoration of plasma fibrinogen to the range of Rewarming on CPB Protamine administration INTEM/HEPTEM Order PLT, FFP or cryoprecipiate, if indicated (Table 3) Confirm coagulopathy and heparin neutralization Hemostatic therapy or additional protamine Evaluate therapeutic response, if indicated, INTEM/HEPTEM/APTEM or PLT function tests Fig 4. Rotational thromboelastometry-based coagulation management in cardiac surgery. Early detection of coagulopathy and preparations for hemostatic therapies are feasible using EXTEM and FIBTEM in the late phase of cardiopulmonary bypass (CPB; at rewarming). Clinical bleeding consistent with coagulopathy can be confirmed after repeating EXTEM and FIBTEM and optimizing heparin neutralization (CT INTEM /CT HEPTEM 1.0). If antifibrinolytic therapy is not used routinely, APTEM can be useful to exclude systemic fibrinolysis as a cause of bleeding. Platelet (PLT) function tests should be considered in patients who recently used aspirin and P 2 Y 12 antagonists. APTEM, modified EXTEM test with aprotinin; CT, coagulation time; EXTEM, tissue factor reagent; FFP, fresh-frozen plasma; FIB- TEM, modified EXTEM test with cytochalasin D; HEPTEM, heparinase plus INTEM reagent; INTEM, ellagic acid reagent. mg/dl (FIBTEM-MCF 8-10 mm; Table 3) with continuous antifibrinolytic therapy. 5,6 Platelet transfusion is used in patients with thrombocytopenia (EXTEM-MCF 45 mm and FIBTEM 8-10 mm) and those with platelet dysfunction from antiplatelet therapy. Preoperative platelet function tests may be helpful to diagnose and manage bleeding related to platelet dysfunction. 30,32 In patients who continue preoperative vitamin K antagonist therapy and in those who underwent extensive hemodilution or cell salvage, plasma or PCC may be necessary to restore procoagulant zymogens. EXTEM-CT values 100 seconds may indicate a procoagulant factor deficiency, particularly FVII, FIX, FX, and prothrombin (Table 3). INTEM-CT values 240 seconds also may be used to diagnose procoagulant factor deficiency, but excess heparin or protamine can prolong INTEM-CT. 43 As much as ml/kg of plasma may be required to correct moderate-to-severe factor deficiency, 95 whereas PCC can be given in smaller volumes (80 ml per 25-IU/kg dose for an 80-kg person) to supplement key hemostatic factors. 96,97 In patients who required acute vitamin K antagonist reversal for cardiac surgery, PCC was shown to be hemostatically more effective by increasing plasma FX and prothrombin levels compared with FFP. 91,98 Additional clinical studies are necessary to establish the safety and efficacy of plasma-derived and recombinant factor concentrates in combination with conventional plasma and platelet transfusions. The transfusion protocol based on ROTEM and TEG should be useful in the evaluation of coagulopathy and in the patient-specific allocation of transfusion products in cardiac surgical patients. 2,22,23,48,50,51

8 8 TANAKA ET AL Initiation of DCR APTEM APTEM APTEM DCR with ROTEM-modified hemostatic therapy Surgical intervention, if necessary Order PLT, FFP or cryoprecipiate, if indicated (Table 3) Evaluate therapeutic response, if indicated, add antifibrinolytic therapy Continue monitoring until bleeding stops if indicated, add INTEM or PLT function test Fig 5. Rotational thromboelastometry-based coagulation management in major trauma. At the initiation of a massive transfusion protocol in major trauma patients, the use of / APTEM allows a rapid evaluation of thrombocytopenia, hypofibrinogenemia, and the profibrinolytic state. Specific component replacement and antifibrinolytic therapy can be included in the damage control resuscitation (DCR). Rotational thromboelastometric (ROTEM) assessment can be repeated during and after surgical intervention, if indicated. For persistent microvascular bleeding, platelet (PLT) function testing should be considered to evaluate the defect in the primary hemostasis (eg, aspirin and P 2 Y 12 antagonists). AP- TEM, modified EXTEM test with aprotinin; EXTEM, tissue factor reagent; FFP, fresh-frozen plasma; FIBTEM, modified EXTEM test with cytochalasin D; INTEM, ellagic acid reagent. ROTEM-BASED TRANSFUSION ALGORITHMS IN MAJOR TRAUMA Most patients with major traumatic injuries are admitted with various degrees of cardiorespiratory and metabolic disturbances. With an ongoing need for 4 U of erythrocyte concentrates or a blood loss of 150 ml/min, DCR should be triggered to coordinate timely and sufficient provision of blood products (Fig 5). Although damage-control surgery is pivotal to the survival of patients with multiple injuries, 99 massive fluid resuscitation often is required to counter systemic hypoperfusion and worsening acidosis. 20,25 The rapid infusion of crystalloid, albumin, or hydroxyethyl starch can lead to hypothermia and extensive hemodilution of erythrocytes, fibrinogen, and other coagulation factors and inhibitors. 100 It is crucial to prevent the lethal triad of coagulopathy, hypothermia, and acidosis by early resuscitative and hemostatic therapies. In view of dynamic changes in the coagulation system and the paucity of hematologic information (eg, chronic antithrombotic therapy), the use of ROTEM is most practical for the comprehensive assessment of hemostatic function in trauma patients. Initial ROTEM testing using EXTEM, FIBTEM, and APTEM allows a rapid evaluation of thrombocytopenia, hypofibrinogenemia, and the profibrinolytic state (Fig 2). The initial approach based on ROTEM involves the restoration of plasma fibrinogen to the range of mg/dl (FIBTEM-MCF 8-10 mm) using plasma (when a large volume is permitted), cryoprecipitate, or fibrinogen concentrates (Table 3). 4 Platelet transfusion is used in patients with thrombocytopenia (EXTEM-MCF 45 mm) and those with suspected platelet dysfunction. Once residual heparin effects and hypofibrinogenemia are excluded, EXTEM-CT values 100 seconds can be addressed with coagulation factor replacements using plasma or PCC (Table 3). EXTEM-CT seems to be more responsive to hemodilution-induced factor deficiency compared with INTEM-CT or kaolin TEG R-time because increased FVIII in stress shortens contact-activated tests. 16 In severe injury, low EXTEM-MCF values ( 35 mm consistent with thrombocytopenia and hypofibrinogenemia) are accompanied by a profibrinolytic state (ML 15%). 36,37,88 The resolution of clot breakdown on APTEM confirms systemic fibrinolysis (Fig 2), and intravenous administration of tranexamic acid, 1-2 g, should be considered unless ongoing intravascular coagulation is suspected clinically (Table 3). 89 A coexisting hypocoagulable and profibrinolytic state in major trauma seems to indicate the severity of illness, which demonstrates a correlation with mortality. 37,57,88,101 Hemostatic interventions used in DCR are different among trauma centers based on the institutional blood usage policy and the availability of specific components and concentrates. 67,69,102,103 It is acceptable to initiate DCR early using allogeneic plasma and platelet products if the risk of hemorrhagic death is considered high. 25 Once surgical controls of hemorrhage are attained, more individualized, goal-directed (targeted) transfusion is preferred because of the cumulative risks of transfusion, including acute lung injury, multiple organ failure, immunomodulation, thromboembolic complications, infection, and death. 10,12,26,104,105 CONCLUSIONS Timely hemostatic interventions are pivotal in controlling coagulopathy and bleeding after major surgery and trauma. However, the risks of hemorrhage and transfusion-related complications are to be weighed constantly against each other. 12,25,26,104 ROTEM has become increasingly popular in perioperative coagulation management that involves the replacement of multiple coagulation factors. Unlike hereditary hemorrhagic disorders, which usually involve a single factor replacement, perioperative hemorrhage in major surgery and trauma often demands sequential treatments using multiple allogeneic components or factor concentrates. 4-6,83,100 Using the goal-oriented transfusion algorithm, clinicians appropriately may select necessary transfusion component(s) instead of empirically administering all components, with potential hazardous effects. 94 Recent clinical data have supported the use of ROTEM or TEG in evaluating the clinical efficacies of various hemostatic therapies, which had been seldom studied. 64,71,72 Further clinical investigations of hemostatic therapies under the guidance of ROTEM and TEG are warranted to establish the safety, efficacy, and economic impact of various hemostatic components. REFERENCES 1. Despotis GJ, Santoro SA, Spitznagel E, et al: Prospective evaluation and clinical utility of on-site monitoring of coagulation in patients undergoing cardiac operation. J Thorac Cardiovasc Surg 107: , Shore-Lesserson L, Manspeizer HE, DePerio M, et al: Thromboelastography-guided transfusion algorithm reduces transfusions in complex cardiac surgery. Anesth Analg 88: , Mayer SA, Rincon F: Ultra-early hemostatic therapy for acute intracerebral hemorrhage. Semin Hematol 43:S70-S76, 2006

9 ROTEM IN COAGULATION MANAGEMENT 9 4. Schöchl H, Nienaber U, Hofer G, et al: Goal-directed coagulation management of major trauma patients using thromboelastometry (ROTEM)-guided administration of fibrinogen concentrate and prothrombin complex concentrate. Crit Care 14:R55, Girdauskas E, Kempfert J, Kuntze T, et al: Thromboelastometrically guided transfusion protocol during aortic surgery with circulatory arrest: A prospective, randomized trial. J Thorac Cardiovasc Surg 140: , Görlinger K, Dirkmann D, Hanke AA, et al: First-line therapy with coagulation factor concentrates combined with point-of-care coagulation testing is associated with decreased allogeneic blood transfusion in cardiovascular surgery: A retrospective, single-center cohort study. Anesthesiology 115: , Burnouf T, Radosevich M: Nanofiltration of plasma-derived biopharmaceutical products. Haemophilia 9:24-37, Gröner A: Reply. Pereira A. Cryoprecipitate versus commercial fibrinogen concentrate in patients who occasionally require a therapeutic supply of fibrinogen: Risk comparison in the case of an emerging transfusion-transmitted infection. Haematologica 2007;92: Haematologica 93:e24-e26, Engoren MC, Habib RH, Zacharias A, et al: Effect of blood transfusion on long-term survival after cardiac operation. Ann Thorac Surg 74: , Khan H, Belsher J, Yilmaz M, et al: Fresh-frozen plasma and platelet transfusions are associated with development of acute lung injury in critically ill medical patients. Chest 131: , Koch CG, Li L, Sessler DI, et al: Duration of red-cell storage and complications after cardiac surgery. N Engl J Med 358: , Watson GA, Sperry JL, Rosengart MR, et al: Fresh frozen plasma is independently associated with a higher risk of multiple organ failure and acute respiratory distress syndrome. J Trauma 67: , Toulon P, Ozier Y, Ankri A, et al: Point-of-care versus central laboratory coagulation testing during haemorrhagic surgery. A multicenter study. Thromb Haemost 101: , Ganter MT, Hofer CK: Coagulation monitoring: Current techniques and clinical use of viscoelastic point-of-care coagulation devices. Anesth Analg 106: , Segal JB, Dzik WH; Transfusion Medicine/Hemostasis Clinical Trials Network: Paucity of studies to support that abnormal coagulation test results predict bleeding in the setting of invasive procedures: An evidence-based review. Transfusion 45: , Yuan S, Ferrell C, Chandler WL: Comparing the prothrombin time INR versus the APTT to evaluate the coagulopathy of acute trauma. Thromb Res 120:29-37, Borgman MA, Spinella PC, Perkins JG, et al: The ratio of blood products transfused affects mortality in patients receiving massive transfusions at a combat support hospital. J Trauma 63: , Gonzalez EA, Moore FA, Holcomb JB, et al: Fresh frozen plasma should be given earlier to patients requiring massive transfusion. J Trauma 62: , Holcomb JB, Wade CE, Michalek JE, et al: Increased plasma and platelet to red blood cell ratios improves outcome in 466 massively transfused civilian trauma patients. Ann Surg 248: , Brohi K, Cohen MJ, Ganter MT, et al: Acute coagulopathy of trauma: Hypoperfusion induces systemic anticoagulation and hyperfibrinolysis. J Trauma 64: , Despotis GJ, Levine V, Saleem R, et al: Use of point-of-care test in identification of patients who can benefit from desmopressin during cardiac surgery: A randomised controlled trial. Lancet 354: , Nuttall GA, Oliver WC, Santrach PJ, et al: Efficacy of a simple intraoperative transfusion algorithm for nonerythrocyte component utilization after cardiopulmonary bypass. Anesthesiology 94: , Avidan MS, Alcock EL, Da Fonseca J, et al: Comparison of structured use of routine laboratory tests or near-patient assessment with clinical judgement in the management of bleeding after cardiac surgery. Br J Anaesth 92: , Ogawa S, Szlam F, Chen EP, et al: A comparative evaluation of rotation thromboelastometry and standard coagulation tests in hemodilution-induced coagulation changes after cardiac surgery. Transfusion 52:14-22, Holcomb JB: Optimal use of blood products in severely injured trauma patients. Hematology Am Soc Hematol Educ Program 1: , Hannon T: Trauma blood management: Avoiding the collateral damage of trauma resuscitation protocols. Hematology Am Soc Hematol Educ Program 1: , Ho AM, Lee A, Ling E, et al: Agreements between the prothrombin times of blood treated in vitro with heparinase during cardiopulmonary bypass (CPB) and blood sampled after CPB and systemic protamine. Anesth Analg 96:15-20, Urwyler N, Staub LP, Beran D, et al: Is perioperative point-ofcare prothrombin time testing accurate compared to the standard laboratory test? Thromb Haemost 102: , Tanaka KA, Key NS, Levy JH: Blood coagulation: Hemostasis and thrombin regulation. Anesth Analg 108: , Breet NJ, van Werkum JW, Bouman HJ, et al: Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation. JAMA 303: , Breet NJ, van Werkum JW, Bouman HJ, et al: High on-aspirin platelet reactivity as measured with aggregation-based, cyclooxygenase-1 inhibition sensitive platelet function tests is associated with the occurrence of atherothrombotic events. J Thromb Haemost 8: , Ferreiro JL, Sibbing D, Angiolillo DJ: Platelet function testing and risk of bleeding complications. Thromb Haemost 103: , Tanaka KA, Dietrich W: Is it time to implement preoperative platelet function testing before invasive procedures? Br J Anaesth 107: , Craft RM, Chavez JJ, Bresee SJ, et al: A novel modification of the Thromboelastograph assay, isolating platelet function, correlates with optical platelet aggregation. J Lab Clin Med 143: , Afshari A, Wikkelsø A, Brok J, et al: Thrombelastography (TEG) or thromboelastometry (ROTEM) to monitor haemotherapy versus usual care in patients with massive transfusion. Cochrane Database Syst Rev 3:CD007871, Levrat A, Gros A, Rugeri L, et al: Evaluation of rotation thrombelastography for the diagnosis of hyperfibrinolysis in trauma patients. Br J Anaesth 100: , Schöchl H, Frietsch T, Pavelka M, et al: Hyperfibrinolysis after major trauma: Differential diagnosis of lysis patterns and prognostic value of thrombelastometry. J Trauma 67: , Luddington RJ: Thrombelastography/thromboelastometry. Clin Lab Haematol 27:81-90, Venema LF, Post WJ, Hendriks HG, et al: An assessment of clinical interchangeability of TEG and RoTEM thromboelastographic variables in cardiac surgical patients. Anesth Analg 111: , Bolliger D, Seeberger MD, Tanaka KA: Principles and practice of thromboelastography in clinical coagulation management and transfusion practice. Transfus Med Rev 26:1-13, Lang T, Bauters A, Braun SL, et al: Multi-centre investigation on reference ranges for ROTEM thromboelastometry. Blood Coagul Fibrinolysis 16: , 2005

10 10 TANAKA ET AL 42. Lang T, Toller W, Gütl M, et al: Different effects of abciximab and cytochalasin D on clot strength in thrombelastography. J Thromb Haemost 2: , Mittermayr M, Velik-Salchner C, Stalzer B, et al: Detection of protamine and heparin after termination of cardiopulmonary bypass by thrombelastometry (ROTEM): Results of a pilot study. Anesth Analg 108: , Ruggeri ZM: Von Willebrand factor. J Clin Invest 100:S41-S46, Peerschke EI, Zucker MB, Grant RA, et al: Correlation between fibrinogen binding to human platelets and platelet aggregability. Blood 55: , Hornyak TJ, Shafer JA: Interactions of factor XIII with fibrin as substrate and cofactor. Biochemistry 31: , Ni H, Denis CV, Subbarao S, et al: Persistence of platelet thrombus formation in arterioles of mice lacking both von Willebrand factor and fibrinogen. J Clin Invest 106: , Stover EP, Siegel LC, Parks R, et al: Variability in transfusion practice for coronary artery bypass surgery persists despite national consensus guidelines: A 24-institution study. Institutions of the Multicenter Study of Perioperative Ischemia Research Group. Anesthesiology 88: , Karkouti K, Beattie WS, Wijeysundera DN, et al: Recombinant factor VIIa for intractable blood loss after cardiac surgery: A propensity score-matched case-control analysis. Transfusion 45:26-34, Spalding GJ, Hartrumpf M, Sierig T, et al: Cost reduction of perioperative coagulation management in cardiac surgery: Value of bedside thrombelastography (ROTEM). Eur J Cardiothorac Surg 31: , Lee SH, Lee SM, Kim CS, et al: Use of fibrin-based thromboelastometry for cryoprecipitate transfusion in cardiac surgery involving deep hypothermic circulatory arrest during cardiopulmonary bypass. Blood Coagul Fibrinolysis 21: , Larsen OH, Fenger-Eriksen C, Christiansen K, et al: Diagnostic performance and therapeutic consequence of thromboelastometry activated by kaolin versus a panel of specific reagents. Anesthesiology 115: , Lang T, Johanning K, Metzler H, et al: The effects of fibrinogen levels on thromboelastometric variables in the presence of thrombocytopenia. Anesth Analg 108: , Harrison P, Robinson MS, Mackie IJ, et al: Performance of the platelet function analyser PFA-100 in testing abnormalities of primary haemostasis. Blood Coagul Fibrinolysis 10:25-31, Paniccia R, Antonucci E, Maggini N, et al: Assessment of platelet function on whole blood by multiple electrode aggregometry in high-risk patients with coronary artery disease receiving antiplatelet therapy. Am J Clin Pathol 131: , Tantry US, Bliden KP, Gurbel PA: Overestimation of platelet aspirin resistance detection by thrombelastograph PlateletMapping and validation by conventional aggregometry using arachidonic acid stimulation. J Am Coll Cardiol 46: , Carroll RC, Craft RM, Langdon RJ, et al: Early evaluation of acute traumatic coagulopathy by thrombelastography. Transl Res 154: 34-39, Carroll RC, Worthington RE, Craft RM, et al: Post interventional cardiology urinary thromboxane correlates with PlateletMapping detected aspirin resistance. Thromb Res 125:e118-e122, Collyer TC, Gray DJ, Sandhu R, et al: Assessment of platelet inhibition secondary to clopidogrel and aspirin therapy in preoperative acute surgical patients measured by thrombelastography PlateletMapping. Br J Anaesth 102: , Levy JH, Tanaka KA, Dietrich W: Perioperative hemostatic management of patients treated with vitamin K antagonists. Anesthesiology 109: , Rugeri L, Levrat A, David JS, et al: Diagnosis of early coagulation abnormalities in trauma patients by rotation thrombelastography. J Thromb Haemost 5: , Kashuk JL, Moore EE, Le T, et al: Noncitrated whole blood is optimal for evaluation of postinjury coagulopathy with point-of-care rapid thrombelastography. J Surg Res 156: , Alexander DC, Butt WW, Best JD, et al: Correlation of thromboelastography with standard tests of anticoagulation in paediatric patients receiving extracorporeal life support. Thromb Res 125: , Fenger-Eriksen C, Jensen TM, Kristensen BS, et al: Fibrinogen substitution improves whole blood clot firmness after dilution with hydroxyethyl starch in bleeding patients undergoing radical cystectomy: A randomized, placebo-controlled clinical trial. J Thromb Haemost 7: , O Shaughnessy DF, Atterbury C, Bolton Maggs P, et al: Guidelines for the use of fresh-frozen plasma, cryoprecipitate and cryosupernatant. Br J Haematol 126:11-28, American Society of Anesthesiologists Task Force on Perioperative Blood Transfusion and Adjuvant Therapies. Practice guidelines for perioperative blood transfusion and adjuvant therapies: An updated report by the American Society of Anesthesiologists Task Force on Perioperative Blood Transfusion and Adjuvant Therapies. Anesthesiology 105: , German Medical Association: Cross-sectional guidelines for therapy with blood components and plasma derivatives. 4th Revised edition. Transfus Med Hemother 36: , Fries D, Innerhofer P, Perger P, et al: Coagulation management in trauma-related massive bleeding Recommendations of the Task Force for Coagulation (AGPG) of the Austrian Society of Anesthesiology, Resuscitation and Intensive Care Medicine (OGARI). Anaesthesiol Intensivmed Notfallmed Schmerzther 45: , Rossaint R, Bouillon B, Cerny V, et al: Management of bleeding following major trauma: An updated European guideline. Crit Care 14:R52, Levy JH, Szlam F, Tanaka KA, et al: Fibrinogen and hemostasis: A primary hemostatic target for the management of acquired bleeding. Anesth Analg 114: , Miller BE, Mochizuki T, Levy JH, et al: Predicting and treating coagulopathies after cardiopulmonary bypass in children. Anesth Analg 85: , Rahe-Meyer N, Pichlmaier M, Haverich A, et al: Bleeding management with fibrinogen concentrate targeting a high-normal plasma fibrinogen level: A pilot study. Br J Anaesth 102: , Abshire T, Kenet G: Recombinant factor VIIa: Review of efficacy, dosing regimens and safety in patients with congenital and acquired factor VIII or IX inhibitors. J Thromb Haemost 2: , Levi M, Levy JH, Andersen HF, et al: Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med 363: , Butenas S, Brummel KE, Branda RF, et al: Mechanism of factor VIIa-dependent coagulation in hemophilia blood. Blood 99: , Wasowicz M, Meineri M, McCluskey SM, et al: The utility of thromboelastography for guiding recombinant activated factor VII therapy for refractory hemorrhage after cardiac surgery. J Cardiothorac Vasc Anesth 23: , Lak M, Scharling B, Blemings A, et al: Evaluation of rfviia (NovoSeven) in Glanzmann patients with thromboelastogram. Haemophilia 14: , Sørensen B, Johansen P, Christiansen K, et al: Whole blood coagulation thrombelastographic profiles employing minimal tissue factor activation. J Thromb Haemost 1: , 2003